Advanced glycosylation end-products of proteins (AGES) have been implicated in a variety of disorders including complications associated with diabetes and normal aging. AGEs are nonenzymatically glycosylated proteins which have been shown to accumulate in vascular tissue in aging and at an accelerated rate in individuals with diabetes. Particularly, AGEs result from the non-enzymatic, but concentration dependant interaction of glucose and other reducing sugars with amino groups on proteins to form glycosylated proteins termed Amadori adducts. Over time, these Amadori adducts undergo additional rearrangements, dehydrations and cross-linking with other proteins to accumulate as a family of complex structures referred to as AGEs.
AGEs have been shown to bind specifically in a saturable and reversible manner to cell surface receptors, including receptors expressed on the surface of endothelial cells and particularly those of the microvasculature, monocytes/macrophages, smooth muscle cells, mesengial cells and neurons.
Following binding to cell surface receptors, AGEs are taken up in vesicles and either degraded intracellularly or transported through the cells and deposited in the sub-endothelial matrix, where they accumulate. Esposito et al., J. Exp. Med. 170:1387-1407 (1989). In addition, chemotactic signals for monocytes, but not other white cells are released. These monocytes then adhere and diapedese through the endothelial cell layer. Kirstein et al., Proc. Nat'l Acad. Sci. USA 187:9010-9014 (1990).
AGEs also have been shown to cause proliferation of endothelial cells, which become more permeable and more thrombogenic, i.e., thrombomodulin is downregulated while tissue factor is upregulated. Esposito et al., J. Exp. Med. 170:1387-1407 (1989).
Monocytes macrophages can also take up AGEs through their receptors which are distinct from the acetyl-LDL receptors, but which may be related to the receptors for aldehyde-modified proteins. Takata et al., J. Biol. Chem. 263:14819-14825 (1988), Takata et al., Biochim. Biophys. Acta 986:18-26 (1989), Radoff et al., Diabetes 39:1510-1518 (1990). Binding of AGEs to monocytes in vitro leads to the induction of cytokines, TNF and IL-1, which then stimulate the release of a number of other growth factors responsible for cell proliferation, migration and matrix synthesis. Vlassara et al., Science 240:1546-1548 (1988). Increased synthesis of matrix proteins in response to AGEs binding has also been demonstrated for mesangial cells. Skolnick et al., J. Exp. Med. 174:931-939 (1991), Doi et al., Proc. Nat'l Acad. Sci. USA 89:2873-2877 (1992).
Evidence has indicated that the binding of AGEs to their receptors either directly or indirectly induces inflammatory responses in vessel walls, which can trigger or aggravate the pathogenesis of diabetic macro- or microangiopathy. For an overview of the effects of AGEs, see, e.g., Vlassara et al., Laboratory Invest. 70(2):138-151 (1994). Stern et al., J. Biol. Chem. 267:14998-15004 (1992) has reported similarities between RAGE proteins and the Ig superfamily molecules.
Because of the effects AGEs may have in the pathogenesis of a number of disorders, it would generally be desirable to provide compositions and methods to block or otherwise inhibit these effects, and particularly the interaction between AGEs and their cell surface receptors. The present invention meets these and a variety of other needs.